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Anti-Inflammatory Lipid Mediators in Asthma

哮喘中的抗炎脂质介质

基本信息

批准号：
9769851
负责人：
Bruce Alan Freeman
金额：
$ 74.34万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-05 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769851
关键词：
Acids Affect Alkylation Amino Acids Anti-inflammatory Asthma Bacteria Biochemical Biological Models Blinded Cell physiology Cells Chemicals Chronic Clinical Clinical Research Complement Complex Cross-Over Studies Crossover Design Cyclic GMP Cysteine Data Diet Digestion Drug Kinetics Enzymes Evaluation Expression Profiling FDA approved Fatty Acids Fatty acid glycerol esters Formulation Gene Expression Gene Expression Profile Generations Home environment Homeostasis Human Hyperactive behavior Hypertension Impairment Incidence Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Inflammatory Response Pathway Link Lung Mediating Mediator of activation protein Medical Metabolic Metabolic syndrome Metabolism Metalloproteins Molecular Weight Mus Nature Nitrates Nitric Oxide Nitric Oxide Synthase Nitrites Nitrogen Dioxide Nitrogen Oxides Nitrosation Obese Mice Obesity Oils Oral Organ Oxidation-Reduction Oxides Oxygen PPAR gamma Pathogenicity Pharmaceutical Preparations Pharmacology Phenotype Physiological Placebos Plants Population Post-Translational Protein Processing Proteins Proteome Pulmonary Inflammation Reaction Research Risk Salivary Signal Transduction Site Structure Structure of parenchyma of lung Sulfhydryl Compounds Testing Therapeutic Time Tissues Toxicology Transcription Regulatory Protein Unsaturated Fatty Acids adduct adipokines airway hyperresponsiveness airway inflammation asthmatic asthmatic patient attenuation cytokine design dietary constituent drug candidate genotoxicity in vivo inflammatory milieu insulin sensitivity lipid mediator microbiome mouse model nitration nitroalkene novel therapeutics oxidation phase 1 study phase 1 testing phase 2 designs pre-clinical protein structure function public health relevance receptor response restoration transcription factor volunteer

项目摘要

DESCRIPTION (provided by applicant): Cell signaling actions mediated by reduction-oxidation (redox)-dependent post-translational modifications include the oxidation, glutathionylation, S-nitrosation, and alkylation of cysteine. These reactions intimately link metabolic and inflammatory status with changes in cell and organ function, since many enzymes, receptors and transcriptional regulatory proteins mediating metabolic and inflammatory responses contain functionally- significant hyperactive cysteine thiols. Particular focus is being placed on reaction mediated by nitric oxide (NO), nitrite (NO2-) and nitrate (NO3-) and secondary nitrogen oxides and the unique redox signaling responses they induce via fatty acid nitration reactions. The nature and amounts of various nitrogen oxides generated endogenously are dependent on inflammatory status, diet, acidic microenvironments and NO3--reducing enter salivary bacterial populations. Many of these products are chemically-reactive and generate protein NO- home complexes, protein Cys-NO adducts (RSNO) and in the research plan, electrophilic fatty acid nitroalkenes (NO2-FA) that readily and reversibly alkylate susceptible protein thiols. The cGMP-independent pleiotropic signaling actions of NO2-FAs induce adaptive tissue responses that include beneficial shifts in adipokine and cytokine expression, restoration of insulin sensitivity and the attenuation of airway hyperactivity. This motivated us to hypothesize that the promotion of nitro-fatty acid signaling alleviates metabolic syndrome-induced hypertension and its pulmonary complications. To test this concept, a de- risked drug strategy will be evaluated by pursuing both mechanistically-revealing model system studies and a blinded crossover design Phase 2 clinical study: Aim #1 - Identify the sites of NO2-FA adduction in the lung tissue of obese mice with airway hyperactivity and define the biochemical and physiological responses to oral NO2-FA administration. Aim #2 - Evaluate the clinical responses of obese asthmatic patients to the orally-administered NO2-FA, 10-nitro-octadeca-9-enoic acid (NO2-OA). We will identify key sites of NO2-FA-induced PTMs in the lungs of obese mice with airway hyperactivity (AHR) and define how this affects redox-sensitive transcription factor (TF) function, gene expression profiles and activities of critical enzyme targets. Current data support that NO2-FA-mediated PTMs promote salutary responses in murine models of pulmonary inflammation and AHR. Both IV and oral formulations of NO2-FA have undergone extensive preclinical toxicology and pharmacokinetics evaluation and are in FDA-approved Phase 1 testing in humans. The physiological and biochemical responses of obese asthmatics to NO2-FA will be studied in a blinded, placebo-controlled crossover study. These responses to NO2-FA are anticipated to be more efficacious than many single-target asthma drugs, because the pleiotropic anti-inflammatory signaling actions of NO2-FA are expected to strike a pharmacological chord, rather than a note, in this complex inflammatory phenotype.